Kate Maresh

A 25-year-old Indian gentleman presented with learning and progressive walking difficulties since age 12. He had been to mainstream school but left at 16 without qualifications. His parents were unaffected with no consanguinity. He had long standing learning difficulties and formal neuropsychometry was not performed. Cranial nerves were normal apart from mild dysarthria. There was a postural tremor of the left hand with spasticity in the right arm and legs. There was mild weakness of the intrinsic hand muscles and mild pyramidal weakness in the legs with no limb ataxia. Triceps and left biceps jerks were present and the right biceps and both supinator jerks absent. Knee and ankle jerks were brisk and the right plantar reflex extensor. Sensory examination was normal. Gait was spastic. MRI brain and spine showed only cerebral atrophy, diffuse thinning of the corpus callosum (TCC) (Fig. 1a) and periventricular hyperintensities (Fig. 1b). EMG revealed a diffuse motor neuronopathy. Complicated hereditary spastic paraplegia (SPG) was diagnosed. Over 2 years increasing pyramidal weakness and distal wasting of the legs developed requiring ankle foot orthoses. Both plantar reflexes became extensor and he lost both ankle jerks. Weakness in the arms progressed slowly with additional mild biceps and finger extension weakness developing. His 19-year-old sister developed problems with tripping and balance 18 months after initial presentation. She became slow and a right hand rest tremor developed. She had no problems at school. There were no cognitive features on bedside testing. Apart from facial hypomimia and hypometric horizontal saccades cranial nerves were normal. There was right hand and leg rest tremor and rigidity at the right wrist with bradykinesia of right finger tapping. The legs were spastic. There was mild weakness of finger extension bilaterally, of the intrinsic muscles in the right hand and mild pyramidal weakness in the legs. Reflexes were normal in the arms, brisk in the legs with an extensor right plantar reflex. Sensory examination was normal. There was mild left hand dysdiadochokinesis but no finger–nose or heel–shin ataxia. Gait was spastic and unsteady. MRI brain showed rostral TCC (Fig. 1c) and periventricular hyperintensities (Fig. 1d). EMG revealed no evidence of denervation. She had a marked response to a Levodopa (L-Dopa) challenge (Table 1) and 6 months later continued to respond to cocareldopa 125 mg t.d.s, with improvement in bradykinesia, tremor and mobility. As her brother had no extrapyramidal features he was not treated with L-Dopa. Spatacsin sequencing in both revealed a known homozygous deletion in exon 4 (c.733_734delAT) [1] causing truncation of the protein (p.Met245ValfsX2), confirming SPG11 (Fig. 1e, f). SPG11 is an important cause of autosomal recessive spastic paraplegia. TCC is most common in SPG11 [1, 2]. C. M. Everett (&) K. E. Maresh Department of Neurology, Royal London Hospital, Whitechapel Road, London E1 1BB, UK e-mail: christopher.everett@bartshealth.nhs.uk

Dystrophin is expressed in brain as well as muscle, and its loss in Duchenne muscular dystrophy (DMD) causes CNS disturbance in addition to muscle pathology. A DMD mouse model (mdx) exhibits exagger- ated fear responses to threat, which normalise with postnatal dystrophin-restoration therapies.To investigate whether fear responses are abnormal in DMD patients, we tested 31 DMD and 25 male control participants aged 7–12 years using a fear conditioning task. Participants viewed trials of two neutral visual stimuli: one ‘safe’ stimulus and one paired with a ‘threat’ (aversive noise) to enable fear condi- tioning. Both stimuli were subsequently presented without the noise to assess extinction of conditioned autonomic fear responses (skin conductance).The initial (unconditioned) response to threat was significantly greater in DMD than controls (p=0.016). Both groups similarly acquired conditioned fear responses (p=0.55). These were retained in controls during early extinction, and later ...

BACKGROUND Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full-length Dp427 is the primary dystrophin isoform expressed in muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS comorbidities is well known, relationships between mutations expected to disrupt Dp140 and Dp71 and motor outcomes are not. METHODS Functional outcome data from 387 DMD boys aged 4-15 years were subdivided by DMD mutation expected effects on dystrophin isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n = 201); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 152); and Group 3 (Dp427/Dp140/Dp71 absent, n = 34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10 m walk/run velocities and rise time velocities were explored using regression analysis. Western blot analysis was used to study Dp427, ...

Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full length Dp427 is the primary dystrophin isoform expressed in skeletal muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS co-morbidities is well known, relationships between lack of Dp140 and Dp71 and DMD motor outcomes are not. We have conducted a series of investigations addressing this. Methods Functional outcome data from 387 DMD boys aged 4.0-15.4 years was subdivided by DMD mutation expected effect on isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n=201); group 2 (Dp427/Dp140 absent, Dp71 present, n=152); and group 3 (Dp427/Dp140/Dp71 absent, n=34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10m walk/run and rise times were explored using regression analysis. We used Capillary Western immunoassay (Wes) analysis to study Dp427, Dp140 and Dp71 production in wild-type and DMD skeletal muscle and myogenic cultures. Grip strength was studied in wild-type, mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD-null (lacking all isoforms) mice. Results In DMD boys, we found a strong association between isoform group and motor function. In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in group 3 than group 1 (p<0.01) and 4.9 points lower in group 3 than group 2 (p=0.05). Mean peak NSAA scores were 4.0 points lower in group 3 than group 1 (p<0.01), 2.4 points lower in group 3 than group 2 (p=0.09) and 1.6 points lower in group 2 than group 1 (p=0.04). Average grip strength in peak force at 3 months of age was higher in mdx than mdx52 mice (p=0.01). Dp427, but not Dp71, was produced in normal skeletal muscle; low levels of Dp71 were detected in DMD skeletal muscle. High Dp71 levels were present in wild-type and DMD myogenic cultures. Conclusions DMD boys lacking Dp140 and Dp140/Dp71 displayed worse motor function with a cumulative effect of isoform loss. DMD mouse models lacking Dp427 and Dp140 had lower grip strength than those lacking Dp427 but not Dp140. Our results highlight the importance of considering the effects of dystrophin isoform loss on DMD motor impairment, with important implications for understanding the complex relationship between brain and muscle function in DMD and patient stratification for clinical trials.

Duchenne muscular dystrophy (DMD) is characterised by loss of dystrophin in muscle. Patients affected by DMD also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length isoform (Dp427) is produced, multiple dystrophin isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3′ end of gene, disrupting the shorter Dp140 and Dp71 isoforms. The mdx mouse model of DMD lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalise with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognised feature of DMD, and its characterisation has implications for improved clinical management and translational research. To inv...

Duchenne muscular dystrophy (DMD), an X-linked childhood-onset muscular dystrophy caused by loss of the protein dystrophin, can be associated with neurodevelopmental, emotional and behavioural problems. A DMD mouse model also displays a neuropsychiatric phenotype, including increased startle responses to threat which normalise when dystrophin is restored in the brain. We hypothesised that startle responses may also be increased in humans with DMD, which would have potential translational therapeutic implications. To investigate this, we first designed a novel discrimination fear-conditioning task and tested it in six healthy volunteers, followed by male DMD (n=11) and Control (n=9) participants aged 7-12 years. The aims of this methodological task development study were to: i) confirm the task efficacy; ii) optimise data processing procedures; iii) determine the most appropriate outcome measures. In the task, two neutral visual stimuli were presented: one safe cue presented alone; o...

Aim: To perform cross-sectional and longitudinal miRNA profiling in plasma from Duchenne muscular dystrophy (DMD) subjects and find non-invasive biomarkers in DMD. Subjects/materials & methods: Plasma was collected from 14 age and sex matched controls and 46 DMD subjects. Free-circulating and extracellular vesicle (EV)-derived miRNA expression was measured by RT-qPCR. Results: Free-circulating and EVs derived miR-29c-3p and miR-133a-3p are dysregulated in DMD subjects. Free-circulating and EV-derived miR-29c-3p are reduced in DMD subjects undergoing daily corticosteroid treatment. Free-circulating miR-1-3p and miR-122-5p are longitudinally upregulated in ambulant DMD subjects. Conclusion: We detected novel free-circulating and EV-derived dysregulated miRNAs in plasma from DMD subjects and characterized the longitudinal profile of free-circulating miRNA on plasma from DMD subjects.

This study investigates whether the salience of the pitch associated with a single reflection of a broadband sound, such as noise, is determined by the monaural information mediated by the stimuli at the two ears, or by the relative locations of the primary sound and the reflection. ...